ALTernative Telomere Maintenance and Cancer

Dilley, Robert L.; Greenberg, Roger A.

doi:10.1016/j.trecan.2015.07.007

Cited by 211 publications

(223 citation statements)

References 114 publications

(117 reference statements)

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“…As mentioned above, telomerase expression is the most common acquired mechanism, but in some cases, ALT pathways are activated to maintain telomere length via DNA repair-recombination activated processes [125]. Telomerase inhibitory therapies are being tested in clinical trials and these treatments are predicted to not work in ALT cancers [126].…”

Section: Atrx As a Therapeutic Target In Gbmmentioning

confidence: 99%

Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

121

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Introduction ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation. Areas covered We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives. Expert opinion ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g., DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

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Section: Atrx As a Therapeutic Target In Gbmmentioning

confidence: 99%

Mutant ATRX: uncovering a new therapeutic target for glioma

Haase

Garcia-Fabiani

Carney

et al. 2018

Expert Opinion on Therapeutic Targets

121

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“…Telomeric DNA strand invasion can occur as either (1) self-strand invasion where the DNA forms ‘t-loops’, 23 displacement loops formed at the telomere ends, or as (2) neighboring strand invasion of sister telomeres, resulting in excessive telomere sister exchanges. A hallmark of ALT—for which there is active assay development for clinical testing 24 —is the formation of circular extrachromosomal telomeric DNA fragments that result from these recombination events, termed C-circles. Interestingly, in disparate bacterial families that harbor linear chromosomes as well as extragenomic linear plasmids, DNA ends are maintained by covalently linking the 3′- and 5′-ends of each terminus to form various closed hairpin structures or by capping chromosome ends with covalently bound terminal proteins 25-28 …”

Section: Solutions To the End-replication Problemmentioning

confidence: 99%

Evolutionary perspectives of telomerase RNA structure and function

2016

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Telomerase is the eukaryotic solution to the ‘end-replication problem’ of linear chromosomes by synthesising the highly repetitive DNA constituent of telomeres, the nucleoprotein cap that protects chromosome termini. Functioning as a ribonucleoprotein (RNP) enzyme, telomerase is minimally composed of the highly conserved catalytic telomerase reverse transcriptase (TERT) and essential telomerase RNA (TR) component. Beyond merely providing the template for telomeric DNA synthesis, TR is an innate telomerase component and directly facilitates enzymatic function. TR accomplishes this by having evolved structural elements for stable assembly with the TERT protein and the regulation of the telomerase catalytic cycle. Despite its prominence and prevalence, TR has profoundly diverged in length, sequence, and biogenesis pathway among distinct evolutionary lineages. This diversity has generated numerous structural and mechanistic solutions for ensuring proper RNP formation and high fidelity telomeric DNA synthesis. Telomerase provides unique insights into RNA and protein coevolution within RNP enzymes.

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“…One of the hallmarks of cancers is their replicative immortality (7). To achieve that, cancer cells have to overcome the telomere dysfunction-induced cell cycle arrest or cell death by adopting one of the two telomere maintenance mechanism (TMMs): (i) 85-90% of cancers reactivate the expression of telomerase (8), and (ii) the remaining 10-15% of cancers use the HR-based ALT pathway (9,10).…”

mentioning

confidence: 99%

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

Pan

Drosopoulos

Sethi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

126

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In the mammalian genome, certain genomic loci/regions pose greater challenges to the DNA replication machinery (i.e., the replisome) than others. Such known genomic loci/regions include centromeres, common fragile sites, subtelomeres, and telomeres. However, the detailed mechanism of how mammalian cells cope with the replication stress at these loci/regions is largely unknown. Here we show that depletion of FANCM, or of one of its obligatory binding partners, FAAP24, MHF1, and MHF2, induces replication stress primarily at the telomeres of cells that use the alternative lengthening of telomeres (ALT) pathway as their telomere maintenance mechanism. Using the telomere-specific single-molecule analysis of replicated DNA technique, we found that depletion of FANCM dramatically reduces the replication efficiency at ALT telomeres. We further show that FANCM, BRCA1, and BLM are actively recruited to the ALT telomeres that are experiencing replication stress and that the recruitment of BRCA1 and BLM to these damaged telomeres is interdependent and is regulated by both ATR and Chk1. Mechanistically, we demonstrated that, in FANCM-depleted ALT cells, BRCA1 and BLM help to resolve the telomeric replication stress by stimulating DNA end resection and homologous recombination (HR). Consistent with their roles in resolving the replication stress induced by FANCM deficiency, simultaneous depletion of BLM and FANCM, or of BRCA1 and FANCM, leads to increased micronuclei formation and synthetic lethality in ALT cells. We propose that these synthetic lethal interactions can be explored for targeting the ALT cancers.aithfully replicating its genome is vital for the fitness and health of a mammalian cell. The replisome frequently encounters a variety of impediments throughout the genome. The temporary/transient slowing or stalling of the replication fork is referred to as replication stress (1, 2). The list of endogenous sources of replication stress is still growing. Nonetheless, the wellrecognized sources of replication stress include unrepaired DNA lesions, mis-incorporated ribonucleotides, unique DNA sequences that are prone to form secondary structures (e.g., G-quadruplex or G4), collision of the replication fork with the transcriptional machinery, an RNA-DNA hybrid (or R-loop) that is formed between a nascent RNA and the adjacent displaced single-stranded DNA (ssDNA), common fragile sites (CFS), and tightly packed genomic regions, such as heterochromatin (2). Because of these constant challenges faced by the replisome, mammalian cells have developed elaborate and complex strategies to resolve the replication stress and ensure the successful completion of DNA replication (1-4).One of the endogenous loci/regions that frequently pose challenges to the replisome is the telomere. Mammalian telomeres are tandem repetitive DNA sequences [the large majority as (TTAGGG) n ] located at the end of every linear chromosome. The addition of TTAGGG is catalyzed by an enzyme called telomerase, a large ribonucleoprotein complex with reverse tr...

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ALTernative Telomere Maintenance and Cancer

Cited by 211 publications

References 114 publications

Mutant ATRX: uncovering a new therapeutic target for glioma

Mutant ATRX: uncovering a new therapeutic target for glioma

Evolutionary perspectives of telomerase RNA structure and function

FANCM, BRCA1, and BLM cooperatively resolve the replication stress at the ALT telomeres

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